Many types of medicines are provided in fluid form, such as a solution or suspension of particles in a propellant or emulsion, and are adapted for oral or nasal inhalation by a patient. As one example, a canister might contain asthma or nasal medicine.
Appropriate medicaments may thus might include, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; antuinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furoate or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, or (−)-4-amino-3,5-dichloro-a-[[[6-[2-(2-pyridinyl)ethoxy] hexyl]methyl] benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the medicament and/or to minimise the solubility of the medicament in the propellant.
Preferred medicaments are selected from albuterol, salmeterol, fluticasone propionate and beclometasone dippropionate and salts or sovates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol.
Medicaments can also be delivered in combinations. Preferred formulations containing combinations of active ingredients contain salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) in combination with an antiinflammatory steroid such as a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate).
During a typical manufacturing process, the canister, which is initially open-topped, is sealed with a top or cap that includes a metering valve. The typical metering valve is actuated by a spring-loaded, hollow valve stem through which a metered or controlled, substantially repeatable dose of medicament is delivered out from the interior of the canister. The seal is effected by crimping the valve cap onto the neck of the canister. The canister is then, many times, charged through the valve stem with an aerosol or other propellant such as CO2, CFC 11, CFC 12, P134A or P227 or combinations thereof, so that the medicament is aerosolized upon delivery out from the canister.
In order to deliver medicine to the patient with suitable efficacy, the canister preferably operates in conjunction with an actuator in a system commonly known as a metered dose inhaler (MDI) unit. The actuator includes a housing having one open end into which a canister is loaded and another open end serving as mouthpiece for the user. A nozzle element is disposed within the housing and includes a valve stem-receiving bore communicating with a nozzle orifice. The orifice is aimed toward the mouthpiece. In order to receive a properly metered dosage of medicine from the canister, the patient installs the canister into the actuator through the canister-loading end until the valve stem is fitted into the receiving bore of the nozzle element. With the canister so installed, the opposite end of the canister typically extends to some degree outside the actuator housing. The patient then places the mouthpiece into his or her mouth and pushes downwardly on the exposed canister end. This action causes the canister to displace downwardly with respect to the valve stem, which in turn unseats the valve. Owing to the design of the valve, the design of the nozzle element, and the pressure differential between the interior of the canister and the ambient air, a short burst of precisely metered, atomized medicine is thereby delivered to the patient.
As known to those skilled in the art, the quality of the manufacturing process of the MDI canister, especially the quality of the crimping process by which the valve cap is sealed onto the canister, is of utmost criticality. Even a slight defect in the resulting crimp will constitute an improperly sealed valve cap. That is, because of the significant pressure differential between the interior of the canister and the ambient air, the slightest leak will render the canister commercially and therapeutically valueless. By the time the defective canister has been distributed to the patient, most or all of the propellant will have escaped the confines of the canister. As a result, the pressure differential is eliminated and the canister rendered inoperative.
In addition, the magnitude of the force (or the range of magnitudes) exerted by the valve cap crimping tool typically utilized in MDI canister production lines is critical in ensuring an effective seal. In general, the act of adjusting the valve assembly crimping equipment on the production lines has been more art than science. As a result, the valve assembly crimping equipment can be improperly adjusted so that the frequency of canister and/or valve assembly defects has the potential to be unacceptably high. On the one hand, too much applied force might crush or otherwise deform the sealing edge of the can. On the other hand, too little applied force might produce a leaking valve and thus fail to create a good seal. Existing, conventional procedures entail a visual inspection of the crimp as well as crude measurements to ensure that the valve seal has been sufficiently compressed. The importance of proper calibration of the crimping equipment is hence well established among those skilled in the art.
One approach employed to verify the integrity of the valve seal has been to incorporate a quality-control mechanism such as a test firing station into the production line. After a canister has passed through the crimping station and a valve assembly has been installed onto the canister, the canister with its valve assembly is transported to a filling station at which a bulk quantity of medicament is conducted into the canister through the valve stem. Subsequently, the filled canister/valve assembly combination is transported to a test firing station. At the test firing station, an operative component bears down on the valve stem to mechanically actuate (or “fire”) the valve assembly so that the operation of the valve assembly can be evaluated. As in the case of the upstream crimping equipment, importance of proper calibration of the test firing equipment is well recognized among those skilled in the art, and for similar reasons. That is, the magnitude of the actuating force imparted by the test firing equipment onto the valve assembly of the canister must fall within a certain accepted range of values. Otherwise, the test firing station may damage the valve assembly and/or the canister, or fail to properly actuate the valve and thus fail to enable a proper verification of manufacturing quality or actuating performance. Therefore, MDI canisters can be needlessly rejected if either too much or too little actuating force is applied at the test firing station.
It would therefore be advantageous to provide a feasible means for identifying and diagnosing problems associated with the manufacture of valve-equipped canisters, and with the assessment of performance of manufactured valve-equipped canisters. In particular, it would be advantageous to provide a feasible means for calibrating the crimping and test firing stations typically employed in MDI unit production lines. The present invention is provided to address these and other problems associated with the assembly of ends, tops or caps onto open-ended canisters, especially the installation of valve assemblies onto such canisters, as well as problems associated with the measurement of various axial forces imparted on canisters during manufacturing processes, such as crimping and actuating forces.